SDF1-3?A is a mutation in an evolutionarily conserved region of the 3?UTR. Our working hypothesis has been that the SDF1-3?A mutation stabilizes the mRNA and thus increases the amount of transcript available for translation. This may result in an increase of SDF-1 available for binding to CXCR4 and a downregulation of surface CXCR4 expression. Careful sequencing of the 5?UTR and the open reading frame have not revealed any other polymorphisms in linkage disequilibrium with SDF1-3?A or associated with rate of disease progression. In collaborative studies, a sensitive assay for determining serum SDF-1 concentrations is being used to quantify serum SDF-1 concentrations in normal donors with the three SDF-1 genotypes. We are also examining the expression of SDF1 by quantifying mRNA SDF1 in stromal cells derived from a normal population. A full length SDF1-3?UTR construct of the wild type and SDF1-3?A UTR differing by a single nucleotide have differential abilities to stabilize mRNA when ligated to a reporter gene. Finally,we are examining the surface expression of CXCR4 using fluorescence activated flow sorting analysis quantification of peripheral blood mononuclear cells from normal donors of the three genotypes. Very preliminary data show a trend of less surface CXCR4 on cells obtained from donors of the SDF1-3?A/SDF1-3?A genotypes compared to individuals carrying the wildtype allele. These experiments are being expanded to include additional SDF1-3?A/SDF1-3?A genotypes which have been identified from a pool of normal donors. Paradoxically, SDF1- 3?A, which appears to recessively protect individuals from developing AIDS in the first decade after infection in our cohorts, has been associated with an increased dominant risk for developing non-Hodgkins lymphoma in a study of HIV-1-infected hemophiliacs and homosexuals, and infants infected by vertical transmission. We have performed a categorical analysis comparing allele and genotype frequencies between HIV seropositive cases with non-Hodgkins lymphoma and controls matched for duration of HIV-1 infection and CD4 T-cell number and have been unable to detect significant differences in allele or genotype frequencies between cases and controls. We have entered into a collaboration to perform survival analyses using Multicenter AIDS Cohort Study seroconverter participants to confirm or refute this clinically important observation. The SDF1 Gene and Progression to AIDS - Chemokines, SDF-1, HIV-1 inhibitor, lymphoma, - Human Tissues, Fluids, Cells, etc.